Creatine, also known as N-(Aminoiminomethyl)-N-methylglycine, methylglycoamine or N-methyl-guanido acetic acid is listed in the MERCK INDEX, an accepted chemical encyclopedia and may be represented by the following depiction: ##STR2## (The Merck Index Tenth Edition, No. 2551). Perhaps, because of the positioning of the --NH.sub.2 group gamma to the carboxylic acid, creatine is labile to acid hydrolysis. Regardless, however, of any purported rational, creatine is susceptible to cyclization under acid conditions to form creatinine which may be represented by the following depiction: ##STR3## In acidic aqueous solutions the formation of creatinine from creatine is nearly quantitative and irreversible (Cannan, Shore, Biochem. J. 22, 924: 1928). Creatinine is, as well, one by-product of normal metabolic use of creatine and has been used as a diagnostic marker of such use. Moreover the exposure of creatine to the acidic environment of the gut would be expected to cause the irreversible formation of creatinine precluding further biological use of ingested creatine. Furthermore, the ingestion of creatine has been associated with marked stomach and gastric upset. Although the ingestion of creatine and gastric upset are perhaps only linked by empirical observation, the acid stability of creatine and subsequent formation of creatinine provide potential reasons.
Muscle contraction and relaxation are fueled by the free energy liberated by the dephosphorylation of adenosine triphosphate (ATP). The ATP stored within cells is rapidly depleted during even normal activity. For normal tissue function to continue, ATP must be rapidly resynthesized from its breakdown products, one of which is adenosine diphosphate (ADP). During maximal exercise of a short duration this resynthesis is accomplished almost exclusively by the anaerobic degradation of phosphocreatine (PCR) and glycogen (Hultman E. et al.; Energy metabolism and fatigue. In: Taylor A, Gollnick P, Green H, et al., eds. Biochemistry of Exercise VII. Champaign, Ill: Human Kinetic Publishers, 1990: vol. 21, 73-92). Greenhaff et al. proposed that the observed decline in force production during intense contraction may be related to the availability of muscle PCR stores (Greenhaff P. L., Casey A., Short A. H., Harris R., Soderlund K., Hultman E.; Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man; Clinical Science (1993) 84,565-571). The depletion of these PCR stores limits the rephosphorylation of ADP, thereby limiting the ATP available for energy production. Greenhaff et al. further proposed that any mechanism capable of increasing the intramuscular total creatine store might arrest PCR depletion during intense muscular contraction and offset or even prevent the decline in the rate of ADP rephosphorylation during exercise. Greenhaff et al. did not document means whereby the effective amount of creatine within the muscle cells could be increased. Indeed, Greenhaff et al. relied upon work previously published by Harris et al. where it was demonstrated that the creatine content of skeletal muscles may be increased, however by only 20-50%, through standard oral pathways. Importantly, in order to achieve this mediocre increase in the creatine content of muscle cells the subjects of the study were required to ingest 20 grams of creatine monohydrate, much of which was washed out through the urine instead of being assimilated and metabolized (Harris RC, Soderlund K, Hultman E.; Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation., Clin. Sci., 1992; 83: 367-74).
Creatine can be found biologically in many forms and in diverse portions of the body. Walker reports creatine to exist mainly in the nerves and muscle (Walker J.B.; Creatine: Biosynthesis. regulation, and function Adv. Enzymology and Related Areas of Molecular Biology (1979) 50: 177-242). Creatine has a normal turnover rate of about 2 grams per day. The biochemical process which uses creatine for the regeneration of ATP from ADP irreversibly transforms creatine to creatinine which is eliminated through the urine. Because creatine is irreversibly used, the body must either produce creatine biochemically or secure an adequate outside source.
Biochemically creatine is synthesized in the human liver and pancreas whereas creatine is synthesized exclusively in the liver by members of the poultry family. The human liver and pancreas use the amino acids glycine, serine, arginine and methionine to synthesize creatine. However, where sufficient creatine is made bioavailable through ingestion such biosynthesis would seem unnecessary. Although animal muscle contains approximately 0.5% creatine by weight, most of this is degraded by cooking thereby precluding cooked meat from the potential list of external sources of ingestible bioavailable creatine. Moreover, neither plant nor vegetable matter provides a source of creatine.
Creatine has been a component in several recent U.S. patents. U.S. Pat. No. 5,397,786 entitled REHYDRATION DRINK discloses and claims a rehydration drink for the treatment and prevention of the loss of essential electrolytes because of fluid loss. This patent teaches that creatine, B vitamins, pantothenic acid and choline are energy enhancers. Additionally, this invention suggests the addition of numerous salts such as MgCO.sub.3, CaCO.sub.3 and magnesium aspartate as supplements which contain essential nutrients for healthy metabolism. However, the use of ionic salts such as MgCO.sub.3 is less effective than desired because most of the ingested element is lost in the acidic environment of the gut.
U.S. Pat. No. 5,576,316 entitled METHOD FOR INHIBITING TUMOR GROWTH RATE USING CREATINE OR CREATINE ANALOGS issued Nov. 19, 1996. This patent teaches the use of creatine and creatine analogs for the treatment of tumors. Specifically this invention teaches that the administration of creatine in the form of a salt can reduce a tumor's growth rate. Importantly, this patent also teaches that significant portions of orally administered creatine are lost through the urine without having been used by the host Although the potential causes for this observance are not stated, one reason could be the low solubility of creatine in water to account for the observed preclusion of ingested creatine from biological use.
Carnitine (3-Carboxy-2-hydroxypropyl)trimethylammnonium hydroxide inner salt (CAR) may be represented graphically according to the depiction of Graphic I. ##STR4##
There are two chemical forms of CAR, L-CAR and D-CAR, of which L-CAR is biologically active and is pharmaceutically available for medicinal indications. Biologically, a portion of CAR binds fatty acids forming acyl (A) CAR while the rest exists as free (F) CAR. The sum of these two fractions is referred to as total (T) CAR Some of its physiological roles in fatty acid oxidation and in the excretion of organic acids have been well investigated.
L-Camitine functions as a carrier molecule in the transport of long chain fatty acids across the inner mitochondrial membrane. It delivers substrate for oxidation and subsequent energy production.
Carnitine's essential role is to transport fatty acids of 12-18 carbons across the outer and inner membranes of the mitochondria. Carnitine palmitoyltransferase catalyzes the transfer of the fatty acid or acyl group to camitine at the outer surface of the mitochondrial membrane. The acylcarnitine then goes across the outer membrane of the inner surface of the mitochondrial membrane. Here the acyl group is transferred back to coenzyme A under the influence of carnitine palmitoyltransferase II (Carnitine Deficiency Dipalma J. R., American Family Physician, 38 (1): 243-251, 1988).
L-Carnitine is used in the treatment of primary systemic carnitine deficiency. Clinical presentation can include recurrent episodes of Reye-like encephalopathy, hypoketotic hypoglycemia, and/or cardiomyopathy. Other associated symptoms included hypotonia, muscle weakness, and failure to thrive (Physicians Desk Reference, 1997, p. 2624).
L-Carnitine may also alleviate the metabolic abnormalities of patients with inborn errors of metabolism that result in the accumulation of toxic organic acids (Physicians Desk Reference, 1997, p.2623).
Carnitine's importance in cardiac metabolism and function has been emphasized by a number of studies showing a close association between systemic and myopathic carnitine deficiency and both hypertrophic and congestive cardiomyopathies (Carnitine Metabolism and Function in Humans. Rebouche C. J., Paulson D. J., Ann Rev 1986. 6: 41-66).
Reports indicate L-Carnitine therapy converts abnormal fatty acid metabolism to normal, increases the concentration of L-Carnitine in cardiac muscle and in blood, and improves cardiac output and blood pressure (L-Carnitine: Its Therapeutic Potential. Dipalma J. R. Amer Fam Phys 34(6): 127-130, 1986).
L-Carnitine may improve exercise tolerance in patients with effort angina (Effects of L-Carnitine on Exercise Tolerance in Patients with Stable Angina Pectoris. Japanese Heart Journal 25: 587, Karikawa T. et al., 1984). L-Carnitine converted lactate production to extraction and increased the percentage of free fatty acid extraction, suggesting a use to improve the metabolism of coronary artery disease patients (The Metabolical Effects of L-Carnitine in Angina Pectoris. Ferrari R., Cucchini F., Visioli O., International Journal of Cardiology 5(1984): 213-216). L-Carnitine has also improved the walking capacity of patients with intermittent claudication (Increases in Walking Distance in Patients with Peripheral Vascular Disease Treated with L-Carnitine. A Double-Blind, Cross-Over Study. Brevetti G., Jannelli V. G., et al. Circulation Vol. 77, No. 4,767-773, April 1988). L-Carnitine may benefit the ischemic myocardium by maintaining tissue levels of free carnitine (Protection of the Ischemic Dog Myocardium with Carnitine. Folts J. D., Shug A. L., Koke J. R., Bittar N., American Journal of Cardiology 41: 1209, 1978).
Patients with type II or type IV hyperlipoproteinemia, when treated with 3 grams of oral carnitine per day, had a marked reduction in serum cholesterol and serum triglyceride (Carnitine. Borum, P. R. Ann Rev Nutr 1983. 3: 233-259).
Carnitine may be an essential nutrient for the newborn (Carnitine. Borum, P. R. Ann Rev Nutr 1983. 3: 233-259). L-Carnitine has promise in reducing the fat accumulation in certain types of fatty livers (L-Carnitine: Its Therapeutic Potential. Dipalma J. R. Amer Fam Phys 34(6): 127-130, 1986). The use of L-Carnitine in dialysis patients may be important in individual cases L-Carnitine: Its Therapeutic Potential. Dipalma J.R. Amer Fam Phys 34(6): 127-130, 1986).
Meat and dairy products are the major sources of carnitine in the United States. Cereal, fruits, and vegetables contain little or no carnitine (Carnitine. Borum, P. R. Ann Rev Nutr 1983. 3: 233-259).
Individuals on enteral nutrition for long periods of time whose protein source is soy protein isolate, casein, or egg white protein get low amounts of carnitine (4 nmol/ml carnitine or less) (Carnitine. Borum, P. R. Ann Rev Nutr 1983. 3: 233-259).
There is evidence of increased VO.sub.2 max with carnitine supplementation. This is probably through the removal of part of the short-chain acyl-CoA by L-Camnitine in the muscles heavily involved in exercise with a concurrent release of free CoA. This would stimulate pyruvate dehydrogenase and enhance flux in the Krebs Cycle (L-Carnitine Supplementation in Humans. The Effects on Physical Performance. Cerretelli P., Marconi C., Int J. Sports Med 11 (1990) 1-14).
L-Carnitine could be advantageous to exercising individuals, as prolonged exercise increases the urinary excretion of carnitine (L-Carnitine Supplementation in Humans. The Effects on Physical Performance. Cerretelli P., Marconi C., Int J. Sports Med 11 (1 990) 1-14).
A positive effect of L-Carnitine is an increase of muscles' anaerobic capacity. Carnitine, by functioning as an acetyl group buffer, 1) Maintains a viable pool of CoA even when the rate of acetyl-CoA formation exceeds that of condensation of the above metabolite with oxaloacetate, 2) Prevent "flooding" of the mitochondrial matrix by acetyl-CoA esters, 3) Act as an additional sink for pyruvate, and 4) Improve the transport of adenine nucleotides (L-Carnitine Supplementation in Humans. The Effects on Physical Performance. Cerretelli P., Marconi C., Int J. Sports Med 11 (1990) 1-14).
L-Carnitine may increase lipid utilization by muscle during exercise. (Decrease in Respiratory Quotient During Exercise Following L-Carnitine Supplementation. Gorostiaga E. M., Maurer C. A., Eclache J. P., Int J. Sports Med. 10 (1989) 169-174.
L-Carnitine has been shown to increase both maximal oxygen uptake and power output (Influence of L-Carnitine Administration on Maximal Physical Exercise. Vecchiet L., et al. European Journal of Applied Physiology (1990) 61: 486-490).
In the supplementation of L-CAR for patients on long-term total parenteral nutrition, especially for patients with short bowel syndrome, a more practical problem arises. Oral supplementation of L-CAR of the type known cannot provide a sufficient amount of CAR when patients have severe malabsorption, because it is not easily absorbed. For this population, intravenous supplementation is considered. However, the availability of L-CAR for intravenous administration is limited because of a lack of metabolically acceptable salts of carnitine.
Carnitine possesses an unpleasant smell and is hygroscopic as a solid. The hygroscopicity makes it very difficult to store carnitine, especially as a solid. The creatine salt of carnitine of the present invention overcomes these problems and possesses a distinct yet pleasant taste and is not hygroscopic.